The Loss of the Y Chromosome
Overview The Y chromosome is an incredibly important chromosome in humans and other mammals, and is principally crucial to the formation of male or female characteristics in the fetal stage of development. Despite being one of the smallest of the chromosomes, it's importance lies in the unique genes that it contains. This is largely dependent on the presence of the Y chromosome specific Sex Determining Region Y (SRY) gene, responsible for the formation of a transcription factor (of the same name) that functions as an activator of male-specific feature genes within a developing fetus.Y Chromosome. Genetics Home Reference. Pub. Date Nov. 24, 2014. [http://ghr.nlm.nih.gov/chromosome/Y Link]SRY. Genetics Home Reference. Pub. Date Nov. 24, 2014. [http://ghr.nlm.nih.gov/gene/SRY Link] The most important of these features being the development of the testis, in which the SRY gene was found (as recently as 1990) to be required for formation of the male sex features through the study of mutation patterns in the genes contained within XY females linking two different single nucleotide mutations to sex reversals in XY females.Berta, P., Hawkins, J.R., Sinclair, A. H., Taylor, A., Griffiths, B. L., Goodfellow, P. N., and Fellous, M. (1990) Genetic evidence equating SRY and the testis-determining factor. Nature 348(6300):448-50. [http://www.ncbi.nlm.nih.gov/pubmed/2247149 Link] Not without its problems, a known issue regarding the Y chromosome is the fact that, given its size and potential for variability, it is disappearing and/or losing its function. This is both happening on a small scale within individuals as well as in the population as a whole. In terms of the individual level, it typically happens through the aging process as there is more potential for somatic cells to mutate or mis-separate chromosomes in division, leading to disease phenotypes with severe health defects.Jobling, M. A. and Tyler-Smith, C. (2000)New uses for new haplotypes the human Y chromosome, disease and selection. Trends Genet. 16(8):356-62. [http://www.ncbi.nlm.nih.gov/pubmed/?term=10904265 PubMed] In the population, years of documented and proposed mutations within the chromosome has led to the prediction that it will eventually lose all function and effectively become extinct. Graves, J.A. (2006)Sex Chromosome Specialization and Degeneration in Mammals. Cell 124(5):901-14. [http://www.ncbi.nlm.nih.gov/pubmed/16530039 PubMed] Individual Scale and Related Effects The loss of the Y chromosome in somatic cells, through function-deleting mutations or non-disjunction, has been implicated in the development of a number of diseases and has been shown to be linked to the advanced age of an individual. This was first shown in a study conducted by Pierre and Hoagland in 1972, in which normal, preleukemic, and leukemic patients were harvested of marrow cells, which were then allowed to divide and were karyotyped for the presence of a "45, X" (missing Y) karyotpe. It was found that this specific karyotype was more prevalent in older individuals and that there was no real correlation between the disease and the karyotype.Pierre, R. V. and Hoagland, H. C. (1972) Age-associated aneuploidy: loss of Y chromosome from human bone marrow cells with aging. Cancer. 30(4):889-94. [http://www.ncbi.nlm.nih.gov/pubmed/?term=4116908 PubMed] More recent studies have come to similar conclusions, but have suggested that the loss of the Y chromosome is definitely correlated to the presence of leukemia while possibly not being related to the actual cause.Wong, A.K., Fang, B., Zhang, L., Guo, X., Lee, S., and Schreck, R. (2008) Loss of the Y chromosome: an age-related or clonal phenomenon in acute myelogenous leukemia/myelodysplastic syndrome? Arch Pathol Lab Med. 132(8):1329-32 [http://www.ncbi.nlm.nih.gov/pubmed/18684036 PubMed] These findings are important as they imply that the loss of the chromosomes in certain cells can lead to a loss of the function that specific genes on the chromosomes performed. Another prominent disease related to Y loss is the development of tumors and cancers. One such cancer is testicular cancer, specifically a gonadoblastoma, thought to be potentially caused by the absence of a potential tumor suppressor gene (Testis-specific protein Y-encoded, TSPY) located on the Y chromosome. This has been thought to lead to the development of tumors as its absence (either the gene or whole chromosome), as one would expect, is one of the mechanisms leading to an increased proliferation of tumor cells within the testis.Lau, Y. F. Gonadoblastoma, testicular and prostate cancers, and the TSPY gene. (1999) Am J Hum Genet. 64(4):921-7. [http://www.ncbi.nlm.nih.gov/pubmed/10090875 Pubmed] Another such cancer that has been linked to the loss of the Y chromosome is prostate cancer, specifically in the deletion of 6 of the 30 functional genes found on the chromosome, by Perinchery and Co-workers in 2000. These chromosomes are the SRY gene, the expression regulating Zinc-finger DNA Binding protein gene (ZFY), sperm cell regulating RNA Binding motif (RBM1), two genes of unknown function (BPY 1 and 2), and a spermatogenesis and antigen generating gene (SMCY). For the study, the researchers amplified DNA taken from radical prostatectomy samples from 50 separate patients and analyzed them for gene deletions using polyacrylamide gel electrophoresis. It was found that in all 50 cases, at least one of the genes in question was deleted in advanced stages of tumorigenesis at varying frequencies, with later stage tumors with higher differentiation generally having a higher deletion frequency. The authors concluded that because all of the genes in question were testis specific and that they could not find occurrence of the expression of the genes linked to cancer, that it could be concluded that their deletion may be a direct influence on prostate cancer.Perinchery. G., Sasaki, M., Angan, A., Kumar, V., Carroll, P., and Dahiya, R. (2000)Deletion of Y-chromosome specific genes in human prostate cancer.J Urol. 163(4):1339-42 [http://www.ncbi.nlm.nih.gov/pubmed/10737540 PubMed] A final example of Y chromosome loss manifesting in a disease phenotype within an individual is the presence of deletions found in infertile men. This typically has to do with deletions in the Y chromosome, specifically in the Azoospermia factor region (AZF) located on the long arm of the y chromosome. Deletions in this region, split up into four subregions (AZFa, AZFb, AZFc, and AZFd) have been found to be highly correlated to having signficant correlations to male infertility. Each region contains a wide array of candidate genes implicated in the phenotype, however the most important gene that has been found in infertile men is the Deleted in Azoospermia (DAZ) gene, as well as members of its family. These proteins are believed to be RNA binding proteins involved in spermatogenesis, and their deletion having the highest correlation and contribution to different types of infertility within the four AZF subregions.Poongothai. J., Gopenath, T.S., and Manonayaki, S. (2009)Genetics of human male infertility. Singapore Med. j. 50(4):336-47. [http://www.ncbi.nlm.nih.gov/pubmed/19421675 PubMed] Large Scale Loss and Predicted Outcomes The Y chromosome has been predicted to be the product of an ancestral degradation of an X chromosome, with a very small amount (roughly 5%) of the original genes retained. It has been proposed that, based on this loss at a predicted rate of roughly 3.3 genes every million years as well as the chromosome's high susceptibility towards deletion due to long strings of repeat sequences, the chromosome itself has a functional life span of about 14 million years in mammals. This is predicted to arise when all of the genes on the chromosome are either inactivated or become redundant through mutation, or are entirely deleted, leading to the chromosome not being kept due to functional irrelevance. Where this proposed extinction may lead is debated to this day, but as Graves brings up in her 2006 review covering the sex chromosomes, nature allowing for the extinction of males means the extinction of humans. In light of this information, it has been shown that a number of species have had similar events that may be comensations for a lost Y chromosome. Specific examples include Drosophila melanogaster's proposed loss of Y chromosome homologous to the X and reformation of one with similar genes found in autosomes that is not involved in sex determination,Carvalho, A.B. (2002) Origin and evolution of the Drosophila Y chromosome. Curr Opin Genet Dev.12(6):664-8. [http://www.ncbi.nlm.nih.gov/pubmed/12433579 PubMed] or the migration of all sex determining genes to different chromosomes in different species of mammal (mostly rodents). Both of these potential events can lead to new "Y" chromosomes to replace the lost, nonfunctional one or a means of circumventing the classic XY system. References